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High Expression of CDCA7 Predicts Tumor Progression and Poor Prognosis in Human Colorectal Cancer

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High Expression of CDCA7 Predicts Tumor Progression and Poor Prognosis in Human Colorectal Cancer MOLECULAR MEDICINE REPORTS 22: 57-66, 2020 High expression of CDCA7 predicts tumor progression and poor prognosis in human colorectal cancer SIMAN LI1*, JIEAN HUANG2*, MENGBIN QIN2, JINXIU ZHANG2 and CUN LIAO3 1Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021; 2Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007; 3Department of Colorectal‑Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China Received April 13, 2019; Accepted February 7, 2020 DOI: 10.3892/mmr.2020.11089 Abstract. Colorectal cancer (CRC) is one of the most fatal Introduction types of cancer worldwide. This study aimed to determine the predictive and prognostic values of cell division cycle Colorectal cancer (CRC) is recognized as one of the most associated protein 7 (CDCA7) in CRC. Firstly, the relationship common and deadly cancers worldwide (1). It occupies an between CDCA7 and CRC was assessed through bioinfor- increasingly important position in the spectrum of cancer, and matics analysis. Subsequently, CDCA7 expression levels were represents the leading cause of cancer-related mortality world- detected in various CRC cell lines, as well as 15 fresh human wide (2,3). Due to the lack of specific clinical symptoms and CRC tissues and their paired adjacent normal colorectal tissues early screening tests, a substantial number of patients with CRC using reverse transcription-quantitative PCR and western blot- are first diagnosed at an advanced stage with metastasis (4). ting. Additionally, immunohistochemical staining was used Furthermore, even if a tumor is resected, CRC recurrence and to determine the levels of CDCA7 in 104 CRC tissues and metastasis may occur after surgery; therefore, the prognosis their paired adjacent normal colorectal tissues. The present of CRC remains poor (5). Thus, it is of great importance to study revealed that CDCA7 expression was upregulated in understand the molecular mechanisms underlying CRC devel- CRC tissues and cell lines. The positive expression rates of opment and to identify novel tumor-associated biomarkers. CDCA7 in normal and CRC tissues were 26.92 and 75.96%, Bioinformatics analysis provides a deeper and more respectively. The intensities of CDCA7 immunostaining were comprehensive understanding of targeted genes, and allows significantly associated with CRC invasion depth, lymph node researchers to identify functional genes for further analysis. metastasis, tumor-node-metastasis stage and distant metas- The Cancer Genome Atlas (TCGA) generates comprehensive, tasis. However, no significant differences in sex, age, tumor multi-dimensional maps of the key genomic changes in cancer, size and CRC differentiation were found between high and and provides researchers with a variety of genetic informa- low CDCA7 expression groups. Furthermore, patients with tion on different types of cancer (6). Kyoto Encyclopedia of low CDCA7 expression exhibited a greater overall survival Genes and Genomes (KEGG) (7) and Gene Ontology (GO) (8) rate of CRC compared to those with high CDCA7 expression. analyses have enabled the identification of metabolic signaling The findings of this study indicated that CDCA7 may serve a pathways and major biological functions of differentially significant role in CRC prognosis and progression, and may expressed genes. Therefore, TCGA, data collection, and be considered a novel biomarker for the prediction of patient GO and KEGG pathway enrichment analyses were performed survival after colectomy. in this study. Cell division cycle associated protein 7 (CDCA7) is located on chromosome 2q31 and encodes a nuclear protein containing 371 amino acids (9). CDCA7 is a cell division cycle-associated protein that was first discovered in Myc-transfected fibro- Correspondence to: Dr Cun Liao, Department of Colorectal-anal blasts, which is commonly overexpressed in various types of Surgery, The First Affiliated Hospital of Guangxi Medical human cancer (10). CDCA7 is periodically expressed during University, 6 Shuangyong Road, Nanning, Guangxi 530021, the human cell cycle, with the highest expression level found P. R. Ch i na E‑mail: [email protected] in the G1 to S phase (11). Deregulation of cell cycle proteins often leads to the increased risk of tumor occurrence (12,13). *Contributed equally Previous reports have demonstrated that CDCA7 is a c-Myc-responsive gene that participates in cancer transfor- Key words: cell division cycle associated protein 7, colorectal mation and tumorigenesis (9). Thus far, several studies have cancer, progression, prognosis, bioinformatics analysis reported that CDCA7 is overexpressed in different types of cancer, including lymphoma, ovarian cancer, retinoblas- toma, breast cancer, acute myeloid leukemia and esophageal 58 LI et al: HIGH EXPRESSION OF CDCA7 PREDICTS TUMOR PROGRESSION AND POOR PROGNOSIS IN CRC cancer (10,14‑18). These findings provide evidence that there patterns. The integrated score based on the two predicted may be an association between CDCA7 and tumor develop- scores in the TRANSFAC® database (http://genexplain. ment. However, to the best of our knowledge, the relationship com/transfac/#section3) were assigned as the final predicted between CDCA7 and the development of colorectal disease score. Binding regions of the predicted transcription factors has not yet been reported on. Therefore, the clinical relevance were annotated based on the DNA methylation and single and underlying mechanisms of CDCA7 in the occurrence and nucleotide polymorphism (SNP) information in COSMIC (19) development of CRC remain largely unclear. The present study and dbSNP (https://www.ncbi.nlm.nih.gov/snp/) databases, aimed to investigate the expression levels and clinical role of respectively. According to the predicted scores of the CDCA7 in CRC. TRANSFAC® database and whether the corresponding comment information existed in the COSMIC database and Materials and methods the dbSNP database, the recommendation degree was inte- grated. The recommendation degree was used to represent the Bioinformatics analysis research value of the predicted transcription factor; the higher Collection of CDCA7 expression data from TCGA. the recommendation degree, the better. Results with a high microRNA (miR/miRNA) expression matrix was retrieved recommendation degree were selected for use in the present from TCGA (https://portal.gdc.cancer.gov). RNA‑seq data study. from 647 CRC tissues (cancer group) and 51 normal adja- cent tissues (normal group) were downloaded from TCGA Gene expression in tumors. According to TCGA barcodes, database (dataset nos. TCGA‑COAD and TCGA‑READ). all samples were classified into normal and tumor tissues. Differentially expressed levels of CDCA7 between the cancer Subsequently, the average value and standard deviation of group and normal group were identified using the Ballgown all samples were determined based on the expression values (https://github.com/alyssafrazee/ballgown) package with the in the normalized-results file of each sample provided by following criteria: P<0.05 and fold-change >2. RNA‑SEQv2 data. Finally, the target gene expression in human tumors was interpreted. Gene functions and pathways. KEGG (http://www.genome. jp/kegg/pathway.html) and GO (http://geneontology.org/) Tissue samples. CRC tissues and the paired adjacent were used for the enrichment analysis of dysregulated genes, non-tumor tissues (n=104) in the form of pathological slices in order to determine the changes in functions and pathways were collected from patients (sex, 61 males and 43 females; associated with CRC. The conditional criterion was P<0.05. age, 26-82 years; average age, 56.42±12.87 years) who under- went surgical operation at the Department of Colorectal-anal Research hotspots. According to the gene annotation in the Surgery, The First Affiliated Hospital of Guangxi Medical database, genetic studies were evaluated based on five different University (Guangxi, China) between October 2012 and perspectives: i) Relevant literature of CDCA7 (total number of November 2013. In addition, CRC tissues were collected from articles reported); ii) pathways (number of pathways that CDCA7 15 patients (sex, 9 males and 6 females; age, 47-75 years; was involved in according to the KEGG database); iii) functions average age, 60.33±8.83 years) with pathological confirmation (number of functions that involved the CDCA7 gene according of the diagnosis in November 2017. All tissue specimens were to the GO database); iv) validated targeted miRNAs (number collected within 30 min after surgical resection. The 15 pairs of miRNAs associated with CDCA7 that have been published of CRC tissues and normal adjacent tissues were immediately in literature); and v) diseases (number of diseases associated snap‑frozen in liquid nitrogen, and then stored at ‑80˚C until with CDCA7 that have been published in the literature), in order protein and RNA extraction. The survival status of patients to identify research hotspots of CDCA7 through the KEGG with CRC was verified by telephone interview. None of the and GO databases, and published literature. A radar chart was patients received pre-operative chemoradiotherapy or radio- produced using Microsoft Office 2013 software to demonstrate therapy. Clinicopathological characteristics of the patients the research hotspots of CDCA7 (Fig. 1). were assessed by reviewing patients' medical
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